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    Dose finding and O6-alkylguanine-DNA alkyltransferase study of cisplatin combined with temozolomide in paediatric solid malignancies.

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    Authors
    Geoerger, B
    Vassal, G
    Doz, F
    O'Quigley, J
    Wartelle, M
    Watson, Amanda J
    Raquin, M-A
    Frappaz, D
    Chastagner, P
    Gentet, J-C
    Rubie, H
    Couanet, D
    Geoffray, A
    Djafari, L
    Margison, Geoffrey P
    Pein, F
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    Affiliation
    Department of Pediatrics, Institut Gustave Roussy, Villejuif, France. geoerger@igr.fr
    Issue Date
    2005-09-05
    
    Metadata
    Show full item record
    Abstract
    Cisplatin may have additive activity with temozolomide due to ablation of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (MGMT). This phase I/II study determined recommended combination doses using the Continual Reassessment Method, toxicities and antitumour activity in paediatric patients, and evaluated MGMT in peripheral blood mononuclear cells (PBMCs) in order to correlate with haematological toxicity. In total, 39 patients with refractory or recurrent solid tumours (median age approximately 13 years; 14 pretreated with high-dose chemotherapy, craniospinal irradiation, or having bone marrow involvement) were treated with cisplatin, followed the next day by oral temozolomide for 5 days every 4 weeks at dose levels 80 mg m(-2)/150 mg m(-2) day(-1), 80/200, and 100/200, respectively. A total of 38 patients receiving 113 cycles (median 2, range 1-7) were evaluable for toxicity. Dose-limiting toxicity was haematological in all but one case. Treatment-related toxicities were thrombocytopenia, neutropenia, nausea-vomiting, asthenia. Hearing loss was experienced in five patients with prior irradiation to the brain stem or posterior fossa. Partial responses were observed in two malignant glioma, one brain stem glioma, and two neuroblastoma. Median MGMT activity in PBMCs decreased after 5 days of temozolomide treatment: low MGMT activity correlated with increased severity of thrombocytopenia. Cisplatin-temozolomide combinations are well tolerated without additional toxicity to single-agent treatments; the recommended phase II dosage is 80 mg m(-2) cisplatin and 150 mg m(-2) x 5 temozolomide in heavily treated, and 200 mg m(-2) x 5 temozolomide in less-heavily pretreated children.
    Citation
    Dose finding and O6-alkylguanine-DNA alkyltransferase study of cisplatin combined with temozolomide in paediatric solid malignancies. 2005, 93 (5):529-37 Br. J. Cancer
    Journal
    British Journal of Cancer
    URI
    http://hdl.handle.net/10541/76280
    DOI
    10.1038/sj.bjc.6602740
    PubMed ID
    16136028
    Type
    Article
    Language
    en
    ISSN
    0007-0920
    ae974a485f413a2113503eed53cd6c53
    10.1038/sj.bjc.6602740
    Scopus Count
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    All Paterson Institute for Cancer Research

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